Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula:
is approved under the trademark Zoloft® by the U.S. Food and Drug Administration as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. Only cis sertraline is therapeutically active.
U.S. Pat. No. 4,536,518 (“the '518 patent”) describes the synthesis of sertraline hydrochloride from sertralone having the following formula:

The reported process for synthesizing sertraline from sertralone has two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, 4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H) naphthalenylidene] methanamine (“ketimine”):

The imine is then reduced to sertraline. The formation of cis/trans sertraline hydrochloride from sertralone is described in the following reaction scheme:

The reduction process disclosed in the '518 patent involves the hydrogenation of ketimine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is reported to be a racemic mixture of the cis and trans diastereoisomers (“(±)-cis/trans-sertraline”) in a ratio of approximately 3 to 1.
International Publication WO 99/57093 reports a process of selective hydrogenation with a palladium catalyst pretreated with an alkali halide. The publication reports that the process of the '518 patent may lead to 10% of dechlorinated side products, while the process of the publication has a “total amount of said contaminated by-products . . . below 0.5%.” With regard to the cis/trans ratio, the ratio provided is 85-95% in the description of the invention.
U.S. Pat. No. 6,593,496 reports the preparation of ketimine by reacting sertralone with monomethylamine and either titanium tetrachloride or molecular sieves. The hydrogenation illustrated in scheme 1 is carried out with a palladium catalyst in THF.
US 2003/0105364 reports a process for obtaining optically pure sertralone through chromatography. The examples do not illustrate hydrogenation.
US 2003/0166970 reports a process for making (±)-sertraline with a cis/trans ratio of greater than about 3:1 by hydrogenation of ketimine at a temperature of at least about 40° C. using a palladium or a platinum catalyst.
Two publications, WO 01/30742 and WO 98/27050, report the stereoselective reduction of sertraline imine derivatives. The publication WO 01/30742 reports replacing the methyl group of ketimine with an optionally substituted bulky benzyl group to increase the cis to trans ratio during hydrogenation, followed by the additional steps of converting the bulky group to a methyl group. Additionally, WO 01/30742 reports that “The reduction may be performed using complex hydrides (e.g. NaBH4) or by hydrogenation. Reduction performed by catalytic hydrogenation tends to give better selectivity that reduction using the complex hydrides. For example, aliquots of N-[4-(3,4 dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine were reduced with NaBH4 and Raney nickel/H2 respectively, and subsequently reductively alkylated with formaldehyde, after which the cis/trans ratio was analyzed. The result was a ratio of 53.8/46.2 using NaBH4 compared to 82.9/17.1 for Raney nickel/H2 which clearly demonstrates the selectivity for the catalytic hydrogenation.”
WO 98/27050 reports obtaining sertraline by reducing an N-oxide derivative of the imine. According to Example 1, the N-oxide derivative is hydrogenated with Raney nickel catalyst, while in Example 2a 10% palladium on carbon is used as a catalyst. A cis product with an 81% yield is reported in both instances. According to WO 98/27050, the N-oxide group may then be removed by addition of HCl to the N-oxide compound in ethanol.
WO 01/16089 discloses a process of reductive amination of sertralone to cis and trans sertraline. According to Example 1, sertralone is reduced in the presence of Raney nickel and methylamine. Example 1 reports a yield of 48-51% of the cis isomer.
Typically, hydrogenation of ketimine over Raney Nickel leads to formation of dechlorinated impurities, where dechlorinated impurities are defined as the total amount of sertraline compounds wherein at least one of the two chlorine atoms of the phenyl group is absent. The level of impurities produced depends on the hydrogen pressure, reaction temperature, and duration of hydrogenation. Therefore, control over the level of impurities on a commercial scale is extremely difficult. Furthermore, removal of these impurities is cumbersome due to the same solubility pattern shared by sertraline and the impurities. Loss of the desired material due to additional purification is also a significant obstacle to the hydrogenation process. There is a need in the art for additional processes for hydrogenation of imines for preparation of sertraline.